David Spiegel

Bio: David Spiegel is an academic researcher from Stanford University. The author has contributed to research in topics: Medicine & Breast cancer. The author has an hindex of 106, co-authored 733 publications receiving 46276 citations. Previous affiliations of David Spiegel include Tel Aviv University & University of Adelaide.

Hypnosis and Pain Control

Abstract: Hypnosis, begun as a therapeutic discipline in the eighteenth century, was the first Western conception of a psychotherapy. It is a powerful analgesic, and there is compelling clinical documentation of its effectiveness as far back as the mid-nineteenth century. The British surgeon James Esdaile reported that 80 % of subjects obtained anesthesia with hypnosis during major surgical procedures such as amputations. Hypnosis has been proven effective in treating pain and anxiety in the medical setting using randomized prospective trial methodology among both adults and children. Hypnosis is a state of highly focused attention coupled with a suspension of peripheral awareness. This ability to attend intensely while reducing awareness of context allows one to alter the associational network linking perception and cognition. The hypnotic narrowing of the focus of attention is analogous to looking through a telephoto lens rather than a wide-angle lens – one is aware of content more than context. This can also facilitate reduced awareness of unwanted stimuli, such as pain, or of problematic cognitions, such as depressive hopelessness, that can amplify pain. Such a mental state enhances openness to input from others – often called suggestibility – and can increase receptivity to therapeutic instruction. Yet despite much clinical and neurobiological evidence, hypnosis is rarely used as an analgesic for adults or children.

Activity and safety of ipatasertib (ipat) for AKT activating mutation and/ or PTEN loss/loss of function solid tumors from MyTACTIC

Abstract: Background: MyTACTIC (NCT04632992) is a multiarm basket study evaluating the safety/efficacy of targeted therapies as single agents or combinations in advanced unresectable/metastatic solid tumors with specific genomic alterations. We analyzed the potent oral AKT inhibitor ipat in a pan-tumor population with AKT activating mutation and/or PTEN loss/loss of function from MyTACTIC. Materials and Methods: Enrolled patients (pts) were ≥18 years old and had advanced unresectable/metastatic tumors with AKT1/2/3 mutation and/ or PTEN loss/loss of function alteration. Pts received ipat 400 mg/day. The primary endpoint was investigator-assessed confirmed objective response rate (cORR; complete response [CR]+partial response [PR]). Other key endpoints: disease control rate (DCR; CR+PR+stable disease or non-CR/ non-progressive disease [PD] ≥98 days [28-day arms] or ≥70 days [21-day arms]); progression-free survival (PFS); duration of response (DOR); safety. Results: At data cutoff (Jan 24, 2022), 26 pts with various tumor types had received ipat (AKT activating mutations, n = 5; PTEN, n = 21). Pts had a median of 3 (range 1–8) prior lines of therapy for metastatic disease. cORR was 11.5% (n = 3/26); DCR was 34.6% (n = 9/26). Median DOR was not reached (95% CI 3.7–not estimable); median PFS was 3.6 mos (95% CI 1.9– 7.1). Best overall response per tumor type and AKT/PTEN status is presented in the Table. Adverse events (AEs) were consistent with the known safety profile of ipat. The most common treatment-related AEs (TRAEs) were diarrhea (65.4%) and nausea (30.8%). Grade 3 AEs were seen in 7/26 (26.9%) pts and Grade 4 AEs in 1/26 (3.8%; perirectal abscess) pt; no Grade 5 AE was seen. 2/26 pts (7.7%) had serious TRAEs: 1 pt discontinued treatment due to TRAEs.Table(abstract: 198 (PB078))Cancer TypeTotal n of ptsPR, n (mutation*High-level biomarker listed for PRs only here. Protocol-allowed biomarkers included mutations and PTEN loss via IHC and/or mutation., prior metastatic lines)SD†6 pts had SD >4 months., n (prior metastatic lines)PD, n (prior metastatic lines)Non-CR/non-PD, n (prior metastatic lines)Non Evaluable, nMissing, nBreast71 (AKT1:E17 K, 5+)4 (range 2–5+)1 (3)1Prostate74 (~3–4)2 (4; 5+)1Colon31 (4)2 (3; 4)Colorectal21 (PTEN loss, 3)1 (2)Endometrial21 (PTEN loss, 2)1Rectal11 (1)Anal21 (3)1 (5+)Cervical11 (2)Adenocarcinoma (Neck)11Grand Total, n263810113* High-level biomarker listed for PRs only here. Protocol-allowed biomarkers included mutations and PTEN loss via IHC and/or mutation.† 6 pts had SD >4 months. Open table in a new tab Conclusions: In this small cohort, single-agent ipat showed some clinical activity in heavily pretreated pts with heterogeneous metastatic cancers. Further investigation of the role of AKT inhibition (AKTi) and potential resistance mechanisms is warranted. Given the rationale for AKTi+endocrine therapy (ET) in HR+ HER2– mBC, ipat+ET is being evaluated in the Phase 3 FINER (NCT04650581) and Phase 2 FAIM (NCT04920708) trials. Conflict of interest: Ownership: W.C.D is an employee and shareholder of Roche/Genentech, Inc. W.Y is an employee of Roche/Genentech, Inc. and owns stocks in Roche. Y.K is an employee and shareholder of Roche/Genentech, Inc. T.S is an employee and shareholder of Roche/Genentech, Inc. Advisory Board: A.VW has received advisory board fees from Bristol Myers Squibb, Mirati, and consulting fees from George Clinical, Elsevier. Other Substantive Relationships: A.VW is an employee of Caris Life Sciences. Z.W is an employee of Rutgers University contracted by Genentech, Inc. D.R.S reports consulting paid to the institution from Amgen, AZ, BeiGene, BMS, Curio Science, EMD Serono, Evidera, Exelixis, Genentech/Roche, GlaxoSmithKline, Intellisphere, Janssen, Jazz Pharmaceuticals, Lilly, Mirati Therapeutics, Molecular Templates, Novartis, Novocure, Pfizer, Puma Biotechnology, Regeneron, Sanofi-Aventis research grants to institution from Aeglea Biotherapeutics, Agios, Apollomics, Arcus, Arrys Therapeutics, Astellas, AZ, Bayer, BeiGene, BIND Therapeutics, BioNTech RNA Pharmaceuticals, Blueprint Medicine, Boehringer-Ingelheim, Bristol-Myers Squibb, Calithera, Celgene, Celldex, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, EMD Serono, Evelo Biosciences, G1 Therapeutics, Roche/Genentech, GSK, GRAIL, Hutchison MediPharma, ImClone Systems, Incyte, ImmunoGen, Ipsen, Janssen, Kronos Bio, Lilly, Loxo Oncology, MacroGenics, MedImmune, Merck. Molecular Partners, Molecular Template, Nektar, Neon Therapeutics, Novartis, Novocure, Oncologie, Pfizer, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics, Transgene, UT Southwestern, Verastem. E.A, D.S and R.Z have no conflicts to disclose.

Phase 2/3, randomized, open-label study of an individualized neoantigen vaccine (self-amplifying mRNA and adenoviral vectors) plus immune checkpoint blockade as maintenance for patients with newly diagnosed metastatic colorectal cancer (GRANITE).

Abstract: TPS3635 Background: Treatment options for most patients with metastatic colorectal cancer (mCRC) are largely limited to cytotoxic chemotherapy, with little advancement in the last decade. Encouragingly, a small subset of patients deficient in mismatch repair (dMMR/MSI-hi) benefit from checkpoint inhibitors (CPI) whereas those proficient in mismatch repair (pMMR/MSS) do not. The absence of clinical benefit in patients with pMMR/MSS mCRC may relate to a lack of neoantigen-specific T cells and immune infiltration. An individualized neoantigen vaccine that induces CD8 T cells capable of tumor lysis has the potential to expand the number of patients with mCRC who may benefit from immunotherapy. Data from a Phase 1/2 study evaluating neoantigen vaccines in combination with CPIs in patients with previously treated mCRC demonstrated a 44% molecular response (MR) rate (≥50% decrease in ctDNA relative to baseline) in 4/9 patients; this correlated with improvement in OS relative to those without a MR. To further investigate neoantigen vaccines in earlier lines of treatment, a Phase 2/3 study in the1L maintenance setting in mCRC was initiated. Methods: GO-010 is a Phase 2/3, randomized, open-label, multi-center study evaluating the efficacy and safety of 2 neoantigen-containing vectors (GRT-C901-adenoviral vector plus GRT-R902-self-amplifying mRNA vector) as prime/boost in combination with CPIs as an add-on to fluoropyrimidine/bevacizumab (bev) following 1L therapy with FOLFOX/bev in patients with mCRC. During Phase 2, up to 90 patients will be randomized 1:1 to the vaccine or control arm with a primary objective of assessing efficacy by MR. During Phase 3, up to 226 patients will be randomized with a primary objective of assessing PFS per iRECIST in a blinded, independent manner. There are two stages to the study. In the vaccine production stage, while patients receive FOLFOX/bev 1L therapy, neoantigen prediction is performed using a tumor biopsy and Gritstone’s EDGE™ neoantigen prediction model. For patients in the vaccine arm the top 20 predicted neoantigens are included in the vaccine vectors. After completing oxaliplatin, patients will enter the study treatment stage. Patients in the control arm will continue with maintenance therapy whereas patients in the vaccine arm will add the vaccine regimen to maintenance therapy. The vaccine regimen consists of GRT-C901/GRT-R902 as well as SC ipilimumab (30 mg) and IV atezolizumab (1680 mg). Over the first year of treatment, 6 vaccinations will occur. Ipilimumab will be administered SC with the first doses of GRT-C901 and GRT-R902. Atezolizumab will be administered every 4 weeks for up to 2 years. Study assessments include imaging, ctDNA, safety, immunogenicity and exploratory biomarker analysis. Clinical trial information: NCT05141721.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

The Benefits of Being Present: Mindfulness and Its Role in Psychological Well-Being

Abstract: Mindfulness is an attribute of consciousness long believed to promote well-being. This research provides a theoretical and empirical examination of the role of mindfulness in psychological well-being. The development and psychometric properties of the dispositional Mindful Attention Awareness Scale (MAAS) are described. Correlational, quasi-experimental, and laboratory studies then show that the MAAS measures a unique quality of consciousness that is related to a variety of well-being constructs, that differentiates mindfulness practitioners from others, and that is associated with enhanced selfawareness. An experience-sampling study shows that both dispositional and state mindfulness predict self-regulated behavior and positive emotional states. Finally, a clinical intervention study with cancer patients demonstrates that increases in mindfulness over time relate to declines in mood disturbance and stress. Many philosophical, spiritual, and psychological traditions emphasize the importance of the quality of consciousness for the maintenance and enhancement of well-being (Wilber, 2000). Despite this, it is easy to overlook the importance of consciousness in human well-being because almost everyone exercises its primary capacities, that is, attention and awareness. Indeed, the relation between qualities of consciousness and well-being has received little empirical attention. One attribute of consciousness that has been much-discussed in relation to well-being is mindfulness. The concept of mindfulness has roots in Buddhist and other contemplative traditions where conscious attention and awareness are actively cultivated. It is most commonly defined as the state of being attentive to and aware of what is taking place in the present. For example, Nyanaponika Thera (1972) called mindfulness “the clear and single-minded awareness of what actually happens to us and in us at the successive moments of perception” (p. 5). Hanh (1976) similarly defined mindfulness as “keeping one’s consciousness alive to the present reality” (p. 11). Recent research has shown that the enhancement of mindfulness through training facilitates a variety of well-being outcomes (e.g., Kabat-Zinn, 1990). To date, however, there has been little work examining this attribute as a naturally occurring characteristic. Recognizing that most everyone has the capacity to attend and to be aware, we nonetheless assume (a) that individuals differ in their propensity or willingness to be aware and to sustain attention to what is occurring in the present and (b) that this mindful capacity varies within persons, because it can be sharpened or dulled by a variety of factors. The intent of the present research is to reliably identify these inter- and intrapersonal variations in mindfulness, establish their relations to other relevant psychological constructs, and demonstrate their importance to a variety of forms of psychological well-being.

Standards of Medical Care in Diabetes

Abstract: XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.